WO2007018137A1 - Inhibiteur de multikinase - Google Patents

Inhibiteur de multikinase Download PDF

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Publication number
WO2007018137A1
WO2007018137A1 PCT/JP2006/315465 JP2006315465W WO2007018137A1 WO 2007018137 A1 WO2007018137 A1 WO 2007018137A1 JP 2006315465 W JP2006315465 W JP 2006315465W WO 2007018137 A1 WO2007018137 A1 WO 2007018137A1
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WIPO (PCT)
Prior art keywords
phenol
pyridine
trifluoromethyl
urea
yloxy
Prior art date
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PCT/JP2006/315465
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English (en)
Japanese (ja)
Inventor
Sawako Ozawa
Nobuhiro Oikawa
Eisaku Mizuguchi
Hirosato Ebiike
Fumio Watanabe
Kenji Morikami
Nobuo Shimma
Nobuya Ishii
Toshiyuki Tsukaguchi
Yasuhiro Tamaki
Hidenori Takahashi
Original Assignee
Chugai Seiyaku Kabushiki Kaisha
The University Of Tokyo
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Application filed by Chugai Seiyaku Kabushiki Kaisha, The University Of Tokyo filed Critical Chugai Seiyaku Kabushiki Kaisha
Priority to JP2007529543A priority Critical patent/JP5072595B2/ja
Priority to US11/997,967 priority patent/US8299252B2/en
Priority to EP06782323A priority patent/EP1921078B1/fr
Publication of WO2007018137A1 publication Critical patent/WO2007018137A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Definitions

  • the present invention relates to a novel multikinase inhibitor, a pharmaceutically acceptable salt thereof, a synthetic intermediate of the compound, a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a compound having Raf inhibitory activity and Z or angiogenesis inhibitory action.
  • the compounds are useful for the treatment or prevention of proliferative diseases such as cancer, psoriasis, atherosclerosis, rheumatoid arthritis, endometriosis, diabetic retinopathy, or age-related macular degeneration.
  • kinases that catalyze a substrate-specific phosphorylation reaction exist in human genes! While acting in a complementary manner to phosphatase, which performs the reverse dephosphorylation reaction, the kinase changes the phosphate state of the substrate and regulates its activation state.
  • the network of kinases forms a variety of signal transduction mechanisms in the body, that is, the kinase plays the role of a signal transduction switch.
  • signal transduction is initiated when growth factors bind to receptor tyrosine kinase (RTK) on the cell membrane and RTK autophosphate occurs, and is located downstream of RTK.
  • RTK receptor tyrosine kinase
  • Protein phosphorylation results in various cellular responses, such as metabolism, transcription, proliferation, cell migration, apoptosis, or cell sorting.
  • Non-patent document 2 There are various kinases that are being studied for use as molecular targets. Drugs and antibodies that target ErbBl (EGFRZHER1) and ErbB2 (HER2), which are RTKs, or Bcr, which is a non-RTK Drugs targeting ZAbl have already been put into practical use and used clinically. Others include, for example, kinases involved in the Ras signaling pathway, kinases involved in angiogenesis, and Flt3 kinase. The typical ones are described below.
  • Ras signaling pathway is a pathway that plays an important role in regulating cell growth, differentiation, and transformation. Ras protein activity begins when extracellular signals such as growth factors act on cell surface receptors, and the activated Ras protein interacts with Raf, a serine-threonine protein kinase. Raf is activated (Non-patent document 3 and Non-patent document 4). Raf is known to have three isoforms, A-Raf, B-Raf, and Raf-1 (c-Raf), which interact with Ras protein and the activity of MEK, a substrate. Studies using force knockout mice that differ in terms of the ability of sputum and the distribution of organs in expression have shown that B-Raf and Raf-1 are essential for survival.
  • Raf Activated Raf activates MEK and subsequently MEK activates ERK (MAPK).
  • ERK ultimately activates various substrates in the cytoplasm and nucleus, such as transcription factors, resulting in cellular changes (growth, differentiation, conversion) in response to extracellular signals.
  • This change in cells including proliferation is moderately regulated in normal cells, but in human cancer cells, it is constantly activated by about 20% Ras protein (GTP complex). Mutation has been observed, and as a result, the growth signal to the RafZMEKZERK cascade is maintained, which is known to play an important role in the growth of human cancer cells (Non-patent Document 5).
  • Non-patent document 6 Non-patent document 6
  • RafZ mentioned here In addition to its role as a direct downstream effector of the Ras protein in the MEKZERK cascade, Raf kinase is known to play a central role in inhibiting cellular apoptosis by various mechanisms ( Non-patent document 7 and Non-patent document 8).
  • angiogenesis is an essential process for increasing solid cancer. Cancer cells absorb the necessary oxygen and nutrients in the surrounding environment, but low oxygen, low nutrients, and low pH in areas 1 to 2 mm or more away from the nearest blood vessels resulting from the increase in solid cancer The hypoxia. Cancer cells respond to this stress with the production of various angiogenic factors, stimulating angiogenesis from nearby vascular endothelial cells, allowing further growth. Angiogenesis consists of three steps: 1) destruction of the basement membrane of the vessel wall, 2) migration and proliferation of the endovascular capsule, and 3) lumen formation.
  • VEGF vascular endothelial growth factor
  • b-FGF basic fibroblast growth factor
  • PDGF platelet-derived growth factor
  • VEGF vascular endothelial growth factor
  • VEGFR-1 fit-1
  • VEGFR-2 flk-1, KDR
  • VEGFR-3 fit-4
  • Non-patent Documents 10 and 10 Non-patent Documents 10 and 10
  • Patent Document 11 growth factor receptors other than VE GF, such as FGFR, PDGFR, TIE-2, and cMet, which are involved in angiogenesis, have been suggested to be directly or indirectly involved in angiogenesis.
  • the development of these kinase inhibitors is also being investigated as a therapeutic agent for angiogenic diseases such as cancer (Non-patent Document 12).
  • the Raf kinase mentioned above has also been pointed out as an indirect link with angiogenesis.
  • b-FGF activates Raf-1 by phosphorylating serine 338 and 339 via PAR-1 (p21-activated protein kinase-1), and also protects the apoptotic force independent of MEK1.
  • VEGF signal activates Raf-1 through phosphorylation of tyrosine 340 and 341 via Src kinase and protects endothelial cells in an MEK1-dependent manner.
  • Raf plays a role in controlling the survival of endothelial cells during angiogenesis as well as the growth of cancer cells (Non-patent Document 13).
  • Angiogenesis is an essential physiological phenomenon for fetal embryogenesis, adult wound healing, adult women's menstrual cycle, etc., but abnormal angiogenesis in adult individuals is caused by psoriasis, atherosclerosis, It has been reported to be involved in diseases such as rheumatoid arthritis, endometriosis, diabetic retinopathy, or age-related macular degeneration (Non-Patent Documents 14, 15, and 16), and targets angiogenesis Molecularly targeted drugs are expected to be useful not only for the treatment of cancer, but also for the treatment of diseases associated with these angiogenic abnormalities.
  • FMS—like tyrosine kinase 3 is an RTK belonging to the same family as PDGFR. It is expressed in undifferentiated hematopoietic cells, and binds to the ligand FL, which is expressed in bone marrow and other organs. Transmits survival signals.
  • FLT3 mutations have been found in approximately 30% of acute myeloid leukemia (AML) and approximately 5% of myelodysplastic syndromes (MDS). The type of mutation is internal tandem duplication in the transmembrane region just below the transmembrane region. (lTD) and activation loop (D835) in the kinase domain (Non-patent Document 17). Mutation causes ligand-independent activity, which leads to abnormal growth and transduction of anti-apoptotic signals, especially in the development of acute myeloid leukemia (AML).
  • AML acute myeloid leukemia
  • MDS myelodysplastic syndromes
  • Non-patent Document 20 is an inhibitor of Raf-1 and B-RAF, and also inhibits kinases involved in angiogenesis and cancer progression such as KDR, VEGFR-3, Fit-3, c-KIT, PDGFR-
  • Non-patent Document 21 the compound has high fat solubility and low water solubility, and there is a problem that the difference in pharmacokinetic parameters between patients is large. Problems such as having a tendency to accumulate due to frequent administration have been pointed out.
  • Non-patent document 22 and Non-patent document 23 A serious problem that can easily lead to other problems.
  • Patent Documents 2- 13 a number of urea compounds exhibiting anticancer effects by inhibiting either Raf or angiogenesis-related kinases (eg, KDR, PDGFR, etc.) have been reported (Patent Documents 2- 13).
  • angiogenesis-related kinases eg, KDR, PDGFR, etc.
  • Patent Document 2 a compound having an angiogenesis inhibitory activity based on the inhibition of KDR and the like is reported! /, But Raf-1 inhibitory activity Disclosure is also inevitable.
  • Patent Document 1 International Publication No. 00Z42012 Pamphlet
  • Patent Document 2 Pamphlet of International Publication No. 02Z32872
  • Patent Document 3 Pamphlet of International Publication No. 98Z52559
  • Patent Document 4 Pamphlet of International Publication No.99Z32106
  • Patent Document 5 International Publication No. 99Z32436 Pamphlet
  • Patent Document 6 Pamphlet of International Publication No. 99Z32455
  • Patent Document 7 International Publication No. 02Z62763 Pamphlet
  • Patent Document 8 International Publication No. 02Z85857 Pamphlet
  • Patent Document 9 Pamphlet of International Publication No. 03Z47579
  • Patent Document 10 International Publication No. 03Z68223 Pamphlet
  • Patent Document 11 Pamphlet of International Publication No. 03Z40228
  • Patent Document 12 International Publication No. 03Z40229 Pamphlet
  • Patent Document 13 Pamphlet of International Publication No. 03Z68746
  • Non-Patent Document 1 History of Medicine, 194, 817-823, 2000
  • Non-Patent Document 2 Science, 298th, 1912–1934, 2002
  • Non-Patent Document 3 Trends Biochem. Sci., 19th, 474-480, 1994
  • Non-patent 4 Science, 264th, 1463-1467, 1 year
  • Non-Patent Document 5 Annual Reports in Medicinal Chemistry, 29th, 165-
  • Non-Patent Document 6 Nature, 417, 949, 2002
  • Non-Patent Document 7 Biochemical Pharmacology, 66, 1341-1345, 2003
  • Non-Patent Document 8 Science, 306, pp. 2267-2270, 2004
  • Non-Patent Document 9 Nature, 349, 426-428, 1991
  • Non-Patent Document 10 J. Clinical Oncology, 21st, 60-65, 2003
  • Non-Patent Document 11 Expert Opinion Investigational Drugs, 12th, 51-64, 2003
  • Non-Patent Document 12 Cell Biol., 129th, 895-898, 1995
  • Non-Patent Document 13 Science, 301, pp. 94-96, 2003
  • Non-Patent Document 14 New England Journal of Medicine, No. 333, No. 26, No. 1
  • Non-patent literature 15 Angiogenesis, 5th, 4th, 237-256, 2002
  • Non-patent literature 16 J. Clinical Endocrinology and Metabolism, 89th, 3rd
  • Non-patent document 17 Leuk Lymphoma, 43, 1541-1547, 2002
  • Non-patent document 18 Nature Biotechnology, 23, 6, 237-256, 200
  • Non-Patent Document 19 New Current, Vol. 15, No. 22, pp. 2-13, 2004
  • Non-Patent Document 20 AACR— NCI— EORTC International Conference on Molecular Targets and Cancer Therapeutics Proceedings ⁇ Inings, Brother 69, A 78, 2003
  • Non-Patent Document 21 American Society of Clinical Oncology Annual Meeting (May 18th-May 21st 2002) Abstract, No. 121, No. 1816, No. 1916, 2002
  • Non-Patent Document 22 Pharmazeutician Industrie ⁇ 64 (8), 800-807, 20 02
  • Non-Patent Document 23 Pharmazeutician Industrie 64th (9), 985-991, 20 02
  • the present invention has a high Raf inhibitory activity and angiogenesis inhibitory activity, and is a useful compound for a therapeutic and prophylactic agent effective for diseases associated with pathological angiogenesis and pathological cell proliferation such as cancer and cancer metastasis. It is an object of the present invention to provide a product, a method for producing the product, an intermediate compound useful for the production, and a pharmaceutical composition containing these compounds.
  • the present inventors have excellent Raf inhibitory activity and angiogenesis inhibitory effect, and As a result of diligent search for urea derivative compounds with excellent internal kinetics, derivatives with unique structures have excellent Raf inhibitory activity and angiogenesis inhibitory effect, and highly stable oral absorption, proliferating ability. It was found useful as a prophylactic or therapeutic agent (especially therapeutic agent) excellent in safety against diseases (for example, cancer, cancer metastasis, etc.), and the present invention has been completed.
  • T is — (O) — R;
  • R is C-C alkyl group, C-C cycloalkyl group, C-C alkyl group, C-C
  • Oxotetrahydrothiopyranyl group, 1,1-dioxotetrahydrothiobilyl group and tetrahydroviranyl group are selected; where these groups are a hydroxyl group, an oxo group, a halogen atom and a C— C alkoxy group force is substituted by 1 to 3 independently selected substituents.
  • n 0 or 1;
  • R 2 , R 3 and R 4 are independently a hydrogen atom and C 1 -C alkyl (the alkyl group is
  • R 2 and R 3 together with the urea structure containing the nitrogen atom to which they are attached may form a 5- or 6-membered heterocycle, which is an oxo group or a hydroxyl group.
  • R 2 and R 3 together with the urea structure containing the nitrogen atom to which they are attached can form a 5- or 6-membered heterocycle is selected from oxygen atom, sulfur atom and nitrogen atom 1 or more
  • an oxygen atom may be included as an additional heteroatom.
  • the heterocycle may have a double bond in the ring.
  • R 1 is a -C alkyl group or a tetrahydrobiral group, and these groups are
  • Rogen atom and C—C alkoxy group force are substituted by 1 to 3 independently selected substituents.
  • a compound that may be substituted or a pharmaceutically acceptable salt thereof, or a prodrug thereof is preferred.
  • the compound of the present invention includes a compound having Y force CH in the above formula (I) or a pharmaceutically acceptable salt thereof, or a prodrug thereof. Furthermore, the compound of the present invention includes a compound in which Y is N in the above formula (I) or a pharmaceutically acceptable salt thereof, or a prodrug thereof.
  • cancer psoriasis, atherosclerosis, rheumatoid arthritis, endometriosis and diabetic retinopathy power for the treatment or prevention of selected diseases,
  • a compound of the above formula (I) or a pharmaceutically acceptable salt thereof or a compound thereof Rodrug is provided.
  • a pharmaceutical composition comprising the compound of the above formula (I) or a pharmaceutically acceptable salt thereof, or a prodrug thereof as an active ingredient.
  • a cytostatic action and a Z or a compound comprising the compound of the above formula (I) or a pharmaceutically acceptable salt thereof, or a prodrug thereof are provided.
  • a kinase inhibitor having an anti-angiogenic action is provided.
  • cancer psoriasis, atheroma containing the compound of the above formula (I) or a pharmaceutically acceptable salt thereof, or a prodrug thereof as an active ingredient.
  • age-related macular degeneration comprising the compound of the above formula (I) or a pharmaceutically acceptable salt thereof, or a prodrug thereof as an active ingredient Drugs used for the prevention or treatment of are provided.
  • Drugs used for the prevention or treatment of are provided.
  • the present invention provides a prophylactic or therapeutic agent (especially a therapeutic agent) that not only has an existing Raf inhibition and angiogenesis inhibitory action, but also has excellent pharmacokinetics and safety for proliferative diseases.
  • a prophylactic or therapeutic agent especially a therapeutic agent
  • compounds useful for therapeutic and prophylactic drugs effective for proliferative diseases such as cancer and cancer metastasis, methods for producing the same, intermediate compounds useful for the production, and pharmaceutical compositions containing these compounds Is provided.
  • halogen atom means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom or the like.
  • C C alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms.
  • Means an alkyl group and includes, for example, “C—C alkyl groups” such as methyl, ethyl, n-propyl, i-propyl, n-butyl, sbutyl, i-butyl, t-butyl, and n
  • C C alkyl group means a linear or branched alkyl group having 1 to 3 carbon atoms.
  • alkyl groups i.e. methyl, ethyl, n-propyl and i-propyl.
  • C C cycloalkyl group means a cyclic or moiety having 3 to 8 carbon atoms.
  • a cyclic alkyl group such as cyclopropyl, cyclobutyl, cyclopentyl
  • Cyclopentinoremethinole Cyclopentinoremethinole, cyclopentinoretinole, cyclohexenoremethinole, cyclohexylmethyl and the like.
  • C C alkenyl group means a straight or branched chain having 2 to 6 carbon atoms.
  • C—C alkyl group means a straight or branched chain having 2 to 6 carbon atoms.
  • C—C alkoxy group means a straight chain having 1 to 6 carbon atoms as an alkyl moiety.
  • An alkyloxy group having a chain or branched alkyl group for example, methoxy, ethoxy, n propoxy, i propoxy, n butoxy, s butoxy, i butoxy, t-butoxy, n-pentoxy, 3 methylbutoxy, Includes 2-methylbutoxy, 1-methylbutoxy, 1-ethylpropoxy, n-hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 1-methylpentoxy, 3-ethylbutoxy, and 2-ethylbutoxy It is.
  • C—C alkoxy group means a linear or branched chain having 1 to 3 carbon atoms.
  • Alkoxy group means methoxy, ethoxy, n-propoxy and i-propoxy.
  • C—C alkoxy C—C alkoxy group means the above “C—C alkoxy group”.
  • 1 3 1 3 1 3 is a group in which two“ alkoxy groups ”are bonded, for example, methoxymethoxy, ethoxymethoxy, n— And propoxymethoxy, i-propoxymethoxy, 1-methoxyethoxy, 2-methoxyethoxy and the like.
  • Groups include hydroxyl, oxo, C—C alkoxy, C—C alkoxy, C—C alkoxy,
  • alkyl group substituted with 1 to 3 selected substituents.
  • groups of the group included in the definition include methyl, ethyl, hydroxymethyl, acetyl, and methoxymethyl.
  • R 2 and R 3 are methyl, methoxymethyl and the like
  • preferred groups for R 4 are methyl, methoxymethyl, 2-methoxymonoethoxy. And methyl.
  • R 2 and R 3 can also form a 5- or 6-membered heterocycle together with a urea structure containing a nitrogen atom to which each is bonded, and this 5- or 6-membered ring May contain an oxygen atom as a hetero atom or may contain a double bond, and the substitutable position on the ring is substituted with an oxo group or a hydroxyl group! Can indicate a ring.
  • Examples of such rings include 4,5 dihydroxy-imidazolidine 2one, 4,5 dihydroxy 1,3 dihydro-imidazole 2one, imidazolidine-2,4,5 trione, and the like.
  • the present invention includes a salt of the compound represented by the formula (I) and a pharmaceutically acceptable salt of a prodrug of the compound. These salts are produced by bringing the compound or a prodrug of the compound into contact with an acid or base that can be used in the production of a pharmaceutical product.
  • the salt examples include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, sulfonate, phosphate, phosphonate; acetate, kenate, apple Carboxylates such as acid salts and salicylates; or alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as magnesium salts and calcium salts; ammonium salts, alkyl ammonium salts, dialkyls Ammonium salts such as ammonium salts, trialkyl ammonium salts and tetraalkylquinoleum ammonium salts are included.
  • inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, sulfonate, phosphate, phosphonate
  • acetate kenate
  • apple Carboxylates such as acid salts and salicylates
  • alkali metal salts such as sodium salts
  • a "prodrug” of the present invention is a compound of formula (1) that is converted to a compound of formula (1) or a pharmaceutically acceptable salt thereof by enzymatic or non-enzymatic degradation under physiological conditions. ) Means a derivative of the compound. Prodrugs may be inactive when administered to a patient. Forces are those that are converted into a compound of formula (1) that is active in vivo.
  • the "prodrug” of the present invention includes, for example:
  • the compound of the formula (1) has a carboxyl group in the molecule, it includes an ester group or a substituted compound which is converted to an amide group, and the like.
  • examples of the hydroxyl-protecting group include a C C alkyl carbo group, an aryl carbo group.
  • the protected hydroxyl groups may be natural or non-natural amino acid esters, dipeptide esters, tripeptide esters and tetrapeptide esters.
  • Preferred hydroxyl protecting groups include acetyl groups, glycyl groups, sarkosyl groups, valanyl groups, oral isyl groups, or (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl groups, and the like.
  • Examples of the protecting group for NH group or amino group include C C alkyl carbo yl group,
  • the amino group may be an amide of a natural or non-natural amino acid, an amide of a dipeptide, an ester of a tripeptide and an amide of a tetrapeptide.
  • Preferred protecting groups for amino groups include acetyl groups, glycyl groups, sarkosyl groups, valanyl groups, leucyl groups, or (5-methyl-2-oxo-1,3-dioxolone-4-yl) methyl groups, and the like. included
  • the amino group may be protected to form a saturated or unsaturated heterocyclic group such as a phthalimide group, a succinimide group, a dartarimide group, or a 1 pyrrolyl group.
  • a saturated or unsaturated heterocyclic group such as a phthalimide group, a succinimide group, a dartarimide group, or a 1 pyrrolyl group.
  • the carboxyl group is an ester group or substituted, and is converted to an amide group
  • examples of the ester group include C-C alkyl ester, aryl ester, hetero
  • ester groups include methyl ester groups, ethyl ester groups, 2-hydroxyxetyl esters or 2- (dimethylamino) ethyl ester groups.
  • R 21 and R 22 are preferably a methyl group, an ethyl group, a 2-hydroxyethyl group, or a 2- (dimethylamino) ethyl group.
  • Specific examples of the compound represented by the formula (1) of the present invention include those described below, but the present invention is not limited to these examples.
  • the compound of the present invention represented by the formula (1) is a novel compound not described in any literature, but there are various methods for its production, which can be synthesized using ordinary organic synthesis means. . As a typical example, it can be produced by the following method, for example, but the production method of the compound represented by the formula (1) of the present invention is not limited thereto.
  • the defined group undergoes the desired chemical conversion under the conditions of the implementation method according to the production method shown below, for example, functional group protection, deprotection, etc. Manufacturing can be carried out by using this means.
  • Examples of the protecting group selection and desorption operation include the methods described in “Greene and Wuts, 'Protective Groups in Organic 3 ⁇ 4ythesis (Brother 2nd Edition, John Wiley & 3 ⁇ 4ons 19 91)”. It may be used appropriately according to the conditions. Further, the order of reaction steps such as introduction of substituents can be changed as necessary. In addition, the manufacturing method shown below! On the other hand, after the reaction with the raw material having the functional group as the precursor, the desired product can be obtained by performing the functional group modification reaction at an appropriate stage in the series of reaction steps. Examples of functional group modification reactions include “Smith and March,“ Marchs Advanced Organic and hemistry (5th edition, John Wiley & Sons 2001) ”. ⁇ [MA“!
  • L is a leaving group such as a halogen atom, a nitro group, a methanesulfoloxy group, a trifluoromethanesulfuroxy group, and a ⁇ toluenesulfuroxy group.
  • PG is, for example, a CC alkyl carbo group such as acetyl group, t-butoxy carbo
  • Li represents a protecting group such as a C—C alkylsilyl group.
  • the compound represented by the formula (1) is a known literature (Nicolaou, KC et al., J. Am. Chem. So c., 122, No. 12, 2966-2967, 2000; Macor , E., et al., Tetrahed ron Lett., 40th, 14th, 2733-2736, 1999; Kitterigham, J. et al., Synth. Commun., 30th, 11th, 1937- 1943 Can be produced from the synthesis block (2) and the synthesis block (3) by using a similar method.
  • the arylamine derivative (2) is dissolved in a suitable solvent (eg, dichloromethane, 1,2-dichloroethane, 1,1,2-trichloroethane, THF (tetrahydrofuran), DMF (dimethylformamide), DMSO (dimethylsulfoxide), etc. ), Carbo-Luyre reagent (eg carbonyldiimidazole, phosgene, diphosgene, triphosgene) in the presence or absence of a suitable base (eg pyridine, triethylamine, Hanig base (N, N diisopropylethylamine)).
  • a suitable solvent eg, dichloromethane, 1,2-dichloroethane, 1,1,2-trichloroethane, THF (tetrahydrofuran), DMF (dimethylformamide), DMSO (dimethylsulfoxide), etc.
  • Carbo-Luyre reagent eg carbony
  • the produced active intermediate can be obtained by reacting with the aline derivative (3) after isolation or without isolation. It is also possible to reverse the reaction sequence and react the aline derivative (3) with a carbonylating reagent first, and then react the active intermediate produced with the arylamine derivative (2).
  • the arylate cyanate derivative (4) is obtained from known literature (Knolker, HJ et al., Angew. Chem. Int. Ed. Engl., 34th, 22nd, 2497-2500. Page, 1995) is prepared from the corresponding aromatic amine precursor (2) by using a similar method (step B1).
  • the prepared arylisocyanate derivative (4) is represented by the formula (1) by reacting with an aniline derivative (3) in an appropriate solvent (eg, dichloromethane, THF) with or without isolation. Is obtained (step B2).
  • the arylene isocyanate derivative (5) is prepared by the method of production method 1 2 Prepared from aromatic amine precursor (3a) (Step CI).
  • the arylisocyanate derivative (5) can be reacted with the arylene derivative (2) in an appropriate solvent (eg, dichloromethane, THF) with or without isolation, followed by deprotection of the protecting group with the next step.
  • an appropriate solvent eg, dichloromethane, THF
  • Pillow mouth [2, 3-b] pyridine or pyrazo mouth [3, 4-b] pyridine is oxidized to the corresponding pillow mouth [2, 3-b] pyridine N-oxide or pyrazo mouth [3, 4-b] pyridine N—This is how to get a gift.
  • These substituted pyridines can be obtained in a solvent (for example, dichloromethane, ethyl acetate, 1, and the like) according to a method described in a known literature (Merour et al., Curr. Org. Chem., 5th, 471, 2001) or a similar method.
  • 2-dimethoxyethane, etc. 2-dimethoxyethane, etc. and an appropriate oxidant (eg m-peroxybenzoic acid, peracetic acid, peroxyhydrogen, etc.) in the presence of substituted pyridine N-oxide.
  • an appropriate oxidizing agent for example, hydrogen peroxide, hydrogen peroxide, hydrogen peroxide, urea complex, etc.
  • a catalyst eg methyltrioxorhenium, phthalic anhydride, etc.
  • Pillow mouth [2, 3-b] pyridine N-oxide or pyrazo mouth [3, 4-b] Pyridine mouth with a suitable leaving group at the 4-position [2, 3-b] This is a method for obtaining pyridine or 4-substituted pyrazolo [3, 4-b] pyridine.
  • a suitable leaving group for example, fluorine atom, chlorine atom, bromine atom, etc.
  • a suitable leaving group can be introduced at the 4-position from [2, 3-b] pyridine N-oxide or pyrazo-mouth [3, 4-b] pyridine N-oxide .
  • a protecting group is introduced into the nitrogen atom of the 5-membered ring part of the 4-substituted pyromouth [2, 3-b] pyridine or the 4-substituted pyrazomouth [3, 4-b] pyridine.
  • the introduction of a protecting group is not always necessary in the next step, but it is desirable to introduce the ability to improve yield and operability.
  • the protecting group for example, benzyloxymethyl group, 2- (trimethylsilyl) ethoxymethyl group, benzyl group, p-methoxybenzyl group and the like can be used.
  • Nitrogen with a protecting group on the nitrogen of the 5-membered ring part or unprotected 4-substituted pyro- [2,3-b] pyridine or 4-substituted pyrazo-mouth [3,4-b] pyridine with an oxygen nucleophilic species eg p-aminophenol
  • P-trophenol e.g., P-trophenol
  • p-bromophenol etc.
  • nitrogen nucleophiles eg p-phenoladiamine, p-troa-rin, p-bromoa-lin
  • sulfur nucleophiles eg p-aminothiophenol, p-trothiophenol
  • the reaction is described in known literature (Ullmann et al., Chem. Ber., 37, 853, 1904, Sawyer et al., Tetrahedron, 56, 5045, 2000, Finet et al., Curr. Org. Chem. , Pp.6, 597, 2002), the classical Ullmann method, the modified Ullmann method and similar methods can be used.
  • the reaction may be performed without a solvent or in a suitable solvent (eg, dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, etc.) using a base (eg, triethylamine, N, N-diisopropylethylamine, pyridine, 2,6-lutidine).
  • a suitable solvent eg, dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, etc.
  • a base eg, triethylamine, N, N-diisopropylethylamine, pyridine,
  • an organic base such as an organic base such as potassium carbonate, cesium carbonate, sodium hydride
  • a catalyst eg, copper catalyst, palladium catalyst, etc.
  • the functional group Q is a -tro group, it can be converted to an amino group by reducing it.
  • a reduction method catalytic reduction using palladium carbon, Raney nickel or the like, or a known organic chemical method using a metal such as iron, zinc or tin or a salt thereof as a reducing agent or a similar method can be used.
  • the functional group Q is a halogen such as a chlorine atom, a bromine atom or an iodine atom, for example, known literature (Hartwig et al., Org. Lett., No. 7, Vol. 6, No. 1165, 2005) Can be converted to an amino group using the method described in 1) or a similar method.
  • step D3 the protecting group introduced in step D3 is deprotected.
  • Deprotection for example, “G ree ne and Wuts, Protective uroups m Organic 3 ⁇ 4ythesis ( a 2
  • Oxygen nucleophilic species for example, sodium alkoxide
  • trobenzene derivatives that have leaving groups (for example, halogen such as fluorine atom, chlorine atom, bromine atom, iodine atom, nitro group, etc.) at 3 or 4 position And forming an ether bond.
  • This reaction is carried out in a solvent at a reaction temperature of 78 ° C. to the boiling point of the solvent in the presence of a base.
  • Bases include sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, calcium hydride, etc.
  • inorganic bases such as pyridine, triethylamine, N, N diisopropylethylamine, lithium diisopropylamide, lithium hexamethyldisilazide, n-butyllithium, sodium amide and the like.
  • solvent include non-reactive tetrahydrofuran, jetinoleethenole, dioxane, tonolene, n-hexane, dimethylenolenomolamide, and the like.
  • a reduction method catalytic reduction using palladium carbon, Raney nickel or the like, or a known organic chemical method using a metal such as iron, zinc or tin or a salt thereof as a reducing agent or a similar method can be used. .
  • a C—C bond formation reaction is performed on an aromatic group having a leaving group (for example, a halogen such as a chlorine atom, a bromine atom, or an iodine atom, a trifluoromethansulfonyloxy group, etc.).
  • a leaving group for example, a halogen such as a chlorine atom, a bromine atom, or an iodine atom, a trifluoromethansulfonyloxy group, etc.
  • a substituted aromatic amine compound, an amino protector of a substituted aromatic amine, a substituted aromatic-tro compound, and the like can be used.
  • a well-known organic chemical method can be used for the C—C bond reaction, for example “Diedrich, F., Stang, PJ Eds,“ Metal-Catalyzed Cross-Coupling Reaction ”(Wiley—VCH 199 8 years)” Sonogashira reaction (for example, Mori et al., Synlett, Vol. 5, p. 649, 2001, etc.), Heck reaction (Chalk et al., J. Org. Chem., Vol. 41, No. 7, p. 1206) 1 976), Suzuki coupling (eg Molander et al., J. Org. Chem., No. 67, No. 24, No. 8424, 2002), etc. S can.
  • step G1 After performing step G1, if necessary, the side chain of the introduced carbon chain is placed in a column or 'smith and March, March s Advanced Organic Chemistry ( Functional group transformation can also be performed by the method described in “5th edition, John Wiley & Sons 2001” or “Richard C. Larock, Comprehensive Organic Transformations (VCH Publishers, Inc. 1989)”.
  • Alcohol power is also a step in the acid-acid reaction of aldehydes.
  • the oxidizing agent include metal salts and metal oxides such as chromium, manganese, and silver, or organic compounds such as dimethyl sulfoxide and Dess-Martin Periodinane (for example, Wavrin et al., Synthesis, Section 3, page 326, 2002).
  • a method using an oxidizing agent can be used.
  • a known organic chemical method for example, Brown, HC, et al., Tetrahedron, 35th page, 567 page, 1979, etc.
  • hydride compounds such as sodium borohydride, lithium lithium borohydride, zinc borohydride, lithium aluminum hydride, diisoptyl aluminum hydride, and selectride can be used.
  • Step G5 or Step G5 ′ is an aromatic amino compound
  • this is a step for introducing a protecting group into the amino group.
  • Protecting groups include, for example, t-butoxycarbol groups, benzyloxycarboro groups, carbamate-based protecting groups such as 2,2,2-trichloroethoxysilane, acetyl groups, and trifluoroacetyl groups.
  • these protecting groups can be introduced by the method described in “ureene and Wuts, Protective Groups m Organic Sythesis” (2nd edition, John Wiley & Sons 1991). I'll do it.
  • fluorinating reagent examples include cetylaminosulfur trifluoride (DAST) (for example, Middleton® WJ et al., J. Org. Chem., 40th, 574, 1975), morpholino sulfur trifluoride (for example, Middleton, WJ et al., J. Fluorine Chem., 43, 405, 1989, etc.) Bis (2-methoxyethyl) aminosulfur trifluoride (eg, Singh et al., J. Fluorine Chem., 116) , P. 23, 2002, etc.), ⁇ Ruensulfol fluoride (for example, Robert et al., J. Med. Chem., 33, 315, 55, 1990, Shimizu et al., Tetrahedron Lett., 26, 35, 4207, 1985, etc.) Etc. can be used.
  • DAST cetylaminosulfur trifluoride
  • morpholino sulfur trifluoride for example
  • the substituent Q When the substituent Q is -tro, it can be converted to an amino group by reduction.
  • As a reduction method a known organic chemical method using a catalytic reduction using palladium carbon, Raney nickel or the like or a metal such as iron, zinc or tin or a salt thereof as a reducing agent or a similar method can be used.
  • the substituent Q In the case where the substituent Q is an amino having a protective group introduced in Step G4 or Step G4, it can be converted to an amino group by deprotecting the protective group. Deprotection can be performed, for example, by the method described in “Greene and Wuts,“ Protective Groups in Organic Sythesis ”(2nd edition, John Wiley & Sons 1991)”.
  • raw material compounds of the compounds of the present invention are novel compounds, and these compounds can be easily synthesized in the same manner as known raw material compounds or using methods known to those skilled in the art.
  • the power showing an example of the method for producing the compound of the formula (I) according to the present invention includes extraction, concentration, distillation, crystallization. It can be carried out by applying ordinary chemical operations such as filtration, recrystallization and various chromatography.
  • the compounds of the present invention and pharmaceutically acceptable salts thereof include all stereoisomers (for example, enantiomers, diastereomers (cis and trans geometric isomers) of the compound represented by the formula (1). ;)), Racemates of the isomers, and other mixtures.
  • the compounds of the invention and their pharmaceutically acceptable salts may also exist in several tautomeric forms, such as the enol and imine forms, the keto and enamine forms, and mixtures thereof. .
  • Tautomers exist in solution as a mixture of tautomeric sets. In the solid form, one tautomer is usually predominant. Although one tautomeric isomer may be described, the present invention includes all tautomers of the compounds of the present invention.
  • the compound according to the present invention When the compound according to the present invention is obtained in a free form, it can be converted into a salt which may be formed by the compound or a hydrate or solvate thereof according to a conventional method.
  • the compound power according to the present invention when obtained as a salt, hydrate or solvate of the compound, it can be converted into a free form of the compound according to a conventional method.
  • the compound according to the present invention or a pharmaceutically acceptable salt thereof has an excellent Raf and angiogenesis inhibitory effect, and also has excellent pharmacokinetics, cancer, psoriasis, atherosclerosis, rheumatoid arthritis, It is useful as a prophylactic or therapeutic agent (especially a therapeutic agent) for diseases selected from endometriosis, diabetic retinopathy and age-related macular degeneration. Furthermore, the compound of the present invention is useful as an agent for preventing or treating solid cancer invasion / metastasis (especially a therapeutic agent).
  • the pharmaceutical composition of the present invention is used as a therapeutic agent for diseases selected from cancer, psoriasis, atherosclerosis, rheumatoid arthritis, endometriosis, diabetic retinopathy and age-related macular degeneration.
  • the administration method is oral, rectal, parenteral (intravenous, intramuscular, subcutaneous), intracisternal, intravaginal, intraperitoneal, intravesical And topical (infusion, powder, ointment, gel or cream) administration and inhalation (oral or nasal spray).
  • the dosage forms include, for example, tablets, capsules, granules, powders, pills, aqueous and non-aqueous oral solutions and suspensions, and non-filled containers adapted to be subdivided into individual doses. Examples include oral solutions.
  • the dosage form can also be adapted to various modes of administration including controlled release formulations such as subdermal implantation.
  • the above-mentioned preparation is produced by a known method using additives such as excipients, lubricants (coating agents), binders, disintegrants, stabilizers, flavoring agents, and diluents.
  • additives such as excipients, lubricants (coating agents), binders, disintegrants, stabilizers, flavoring agents, and diluents.
  • excipients include starches such as starch, potato starch, and corn starch, lactose, crystalline cellulose, calcium hydrogen phosphate, and the like.
  • examples of the coating agent include ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, shellac, talc, carnauba wax, and paraffin.
  • binder examples include polybulurpyrrolidone, macrogol, and the same compounds as the excipient.
  • disintegrant examples include compounds similar to the above-mentioned excipients and chemically modified starch / celluloses such as croscarmellose sodium, sodium carboxymethyl starch, and crosslinked polybulurpyrrolidone. .
  • Examples of the stabilizer include para-benzoic acid esters such as methyl paraben and propyl paraben; alcohols such as chlorobutanol, benzyl alcohol and phenol ethyl alcohol; benzalcoyl chloride; phenol and taresol. Such phenols; thimerosal; dehydroacetic acid; and sorbic acid.
  • para-benzoic acid esters such as methyl paraben and propyl paraben
  • alcohols such as chlorobutanol, benzyl alcohol and phenol ethyl alcohol
  • benzalcoyl chloride such as phenols; thimerosal; dehydroacetic acid; and sorbic acid.
  • flavoring agent examples include commonly used sweeteners, acidulants, fragrances and the like.
  • a solvent for producing the liquid agent ethanol, phenol, black cresol, purified water, distilled water, or the like can be used.
  • surfactant or emulsifier examples include polysorbate 80, polyoxysyl 40 stearate, lauromacrogol and the like.
  • the pharmaceutical composition of the present invention is used as a therapeutic agent for diseases selected from cancer, psoriasis, atherosclerosis, rheumatoid arthritis, endometriosis, diabetic retinopathy and age-related macular degeneration.
  • diseases selected from cancer, psoriasis, atherosclerosis, rheumatoid arthritis, endometriosis, diabetic retinopathy and age-related macular degeneration.
  • the amount of the compound of the present invention or a pharmaceutically acceptable salt thereof varies depending on symptoms, age, body weight, relative health, presence of other medications, administration method and the like. For example, for patients (warm-blooded animals, especially humans), generally effective amounts are as follows.
  • LOOOmg Preferably from 0.1 to: LOOOmg, more preferably from 1 to 400 mg per kg body weight, and daily use is preferably in the range of 10 to 800 mg for adult patients with normal body weight. In the case of a parenteral preparation, it is preferably 0.1 to 1000 mg per kg body weight per day, more preferably 10 to 800 mg per kg body weight. Once again 1 ⁇ Should be divided into several doses and administered according to symptoms
  • the NMR data was expressed in ppm (parts per million: ⁇ ), and the deuterium lock signal of the sample solvent power was referred to.
  • CDI 1, 1 ' Carbo-Luji imidazo
  • reaction solution was refluxed under an argon atmosphere for 3 hours, allowed to cool, diluted with water (500 mL), extracted with ether (170 mL ⁇ 3), and the organic layer was extracted with 1M hydrochloric acid (250 mL ⁇ 2).
  • the aqueous layer was alkalinized with 50% aqueous sodium hydroxide (40 mL) and extracted again with ether (150 mL ⁇ 3).
  • the organic layer was washed with saturated brine and then dried.
  • the aqueous layer was extracted with ethyl acetate, the combined organic layers were washed with saturated brine, and the organic layer was dried (sodium sulfate).
  • This phosphonium salt (385 mg, 0.59 mmol) was dissolved in DCM (10 mL) and 2, 2, 2 trifluoroacetaldehyde monohydrate (69.2 mg, 0.60 mmol), potassium carbonate (82 mg , 0.59 mmol) and 18 crown-6 ether (1.6 mg) were added and stirred at 60 ° C for 70 minutes under reflux.
  • the reaction mixture was partitioned between water (30 mL) and ethyl acetate (50 mL), and the organic layer was washed with saturated brine and concentrated under reduced pressure.

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Abstract

La présente invention propose un composé représenté par la formule (1) : dans laquelle Ar est un groupe arylène destiné à être lié choisi dans la formule suivante (2) : dans laquelle * représente un site de liaison à un atome d'azote et ** représente un site de liaison à T ; T représente -(O)n-R ; R représente un groupe alkyle en C1 -C6 ou similaire ; n représente 0 ou 1; X représente O ou similaire ; R2, R3 et R4 sont indépendamment choisis parmi un atome d'hydrogène ou un alkyle en C1-C3 ; ou R2 et R3 peuvent se joindre conjointement avec une structure d'urée contenant les atomes d'azote auxquels ils se lient pour former un hétérocycle de 5 ou 6 chaînons ; Y représente CH or N, ou un sel pharmaceutiquement acceptable de celui-ci ou un promédicament de celui-ci et une composition pharmaceutique contenant celui-ci.
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WO2011023081A1 (fr) * 2009-08-24 2011-03-03 Ascepion Pharmaceuticals, Inc. Composés d'urée contenant un groupe hétéroaryle 5,6-bicyclique
JP2011506365A (ja) * 2007-12-11 2011-03-03 バイエル・シェーリング・ファルマ・アクチェンゲゼルシャフト アルキニルアリール化合物およびその塩、それらを含む医薬組成物、その製造方法並びにその使用
CN101372475B (zh) * 2008-03-19 2012-01-04 南京工业大学 芳杂环取代的二苯脲类衍生物及其用途
US9975966B2 (en) 2014-09-26 2018-05-22 Chugai Seiyaku Kabushiki Kaisha Cytotoxicity-inducing theraputic agent

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EP2686317A4 (fr) * 2011-03-17 2014-08-20 Selexagen Therapeutics Inc Inhibiteurs des kinases raf
WO2018228920A1 (fr) * 2017-06-13 2018-12-20 Bayer Pharma Aktiengesellschaft Dérivés de pyrrolopyridine substitués
EP3638670B1 (fr) * 2017-06-13 2021-07-21 Bayer Pharma Aktiengesellschaft Dérivés de pyrrolopyridine substitués utilisés en tant que modulateurs de map4k1 pour le traitement de maladies cancéreuses
WO2018228925A1 (fr) * 2017-06-13 2018-12-20 Bayer Pharma Aktiengesellschaft Dérivés de pyrrolopyridine substitués
CN115197130B (zh) * 2022-07-27 2023-06-27 安徽医科大学 一种芳基脲类衍生物及其制备方法与应用

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